中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

骨形态发生蛋白9在门静脉性肺动脉高压中的作用机制

张瑞华 秦婷婷 邵玥明 张雨 温晓玉

引用本文:
Citation:

骨形态发生蛋白9在门静脉性肺动脉高压中的作用机制

DOI: 10.3969/j.issn.1001-5256.2022.03.037
基金项目: 

吉林省科技计划项目基金 (20190201065JC)

利益冲突说明:所有作者均声明不存在利益冲突。
作者贡献声明:张瑞华负责课题设计,资料分析,撰写论文;秦婷婷、邵玥明、张雨参与收集数据,修改论文;温晓玉负责拟定写作思路,指导撰写文章并最后定稿。
详细信息
    通信作者:

    温晓玉,xywen@jlu.edu.cn

Mechanism of action of bone morphogenetic protein 9 in portopulmonary hypertension

Research funding: 

Foundation of Science and Technology Commission of Jilin Province (20190201065JC)

More Information
    Corresponding author: WEN Xiaoyu, xywen@jlu.edu.cn(ORCID: 0000-0003-2109-1557)
  • 摘要: 门静脉性肺动脉高压(POPH)是在门静脉高压基础上出现的肺动脉压力升高。骨形态发生蛋白9(BMP9) 作为BMP家族成员之一,除了具有成骨活性外,还具有保护内皮完整性及维持血管稳态的作用。本文通过回顾POPH发病机制、BMP9生理表达及作用,以及BMP9信号通路及其参与肺动脉高压肺血管重塑的相关研究进展,探讨其成为POPH新型生物标志物的可能,进而协助POPH诊断。

     

  • 图  1  BMP9结构[5]

    注:BMP9合成429个氨基酸前体,包含22个信号肽,297个前结构域和110个成熟蛋白,该前体被丝氨酸内切蛋白酶切割产生成熟蛋白质二聚体,该二聚体与两个前结构域保持非共价结合,形成100 kD复合物。

    图  2  BMP9生理作用

    图  3  BMP9在PAH肺血管重塑中作用

  • [1] TUDER RM, ARCHER SL, DORFMVLLER P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension[J]. J Am Coll Cardiol, 2013, 62(25 Suppl): D4-D12. DOI: 10.1016/j.jacc.2013.10.025.
    [2] THENAPPAN T, ORMISTON ML, RYAN JJ, et al. Pulmonary arterial hypertension: Pathogenesis and clinical management[J]. BMJ, 2018, 360: j5492. DOI: 10.1136/bmj.j5492.
    [3] EVANS JD, GIRERD B, MONTANI D, et al. BMPR2 mutations and survival in pulmonary arterial hypertension: An individual participant data meta-analysis[J]. Lancet Respir Med, 2016, 4(2): 129-137. DOI: 10.1016/S2213-2600(15)00544-5.
    [4] XU XQ, JING ZC. The 6th world symposium on pulmonary hypertension: Focus on updates on definition and clinical classification of pulmonary hypertension[J]. Med J Peking Union Med Coll Hosp, 2018, 9(3): 197-201. DOI: 10.3969/j.issn.1674-9081.2018.03.002.

    徐希奇, 荆志成. 第六届世界肺高血压会议: 聚焦肺高血压定义与诊断分类更新[J]. 协和医学杂志, 2018, 9(3): 197-201. DOI: 10.3969/j.issn.1674-9081.2018.03.002.
    [5] BIDART M, RICARD N, LEVET S, et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain[J]. Cell Mol Life Sci, 2012, 69(2): 313-324. DOI: 10.1007/s00018-011-0751-1.
    [6] LIU YJ, LI T. An excerpt of international liver transplant society Practice guidelines: Diagnosis and management of hepatopulmonary hypertension[J]. J Clin Hepatol, 2016, 32(10): 1838-1842. DOI: 10.3969/j.issn.1001-5256.2020.01.051.

    刘以俊, 李涛. 《2016年国际肝移植学会实践指南: 肝肺综合征与门脉性肺动脉高压的诊断与管理》摘译[J]. 临床肝胆病杂志, 2016, 32(10): 1838-1842. DOI: 10.3969/j.issn.1001-5256.2020.01.051.
    [7] MANTZ FA Jr, CRAIGE E. Portal axis thrombosis with spontaneous portacaval shunt and resultant cor pulmonale[J]. AMA Arch Pathol, 1951, 52(1): 91-97. http://www.ncbi.nlm.nih.gov/pubmed/14837570
    [8] BADESCH DB, RASKOB GE, ELLIOTT CG, et al. Pulmonary arterial hypertension: Baseline characteristics from the REVEAL Registry[J]. Chest, 2010, 137(2): 376-387. DOI: 10.1378/chest.09-1140.
    [9] MANCUSO L, SCORDATO F, PIERI M, et al. Management of portopulmonary hypertension: New perspectives[J]. World J Gastroenterol, 2013, 19(45): 8252-8257. DOI: 10.3748/wjg.v19.i45.8252.
    [10] SAVALE L, SATTLER C, COILLY A, et al. Long-term outcome in liver transplantation candidates with portopulmonary hypertension[J]. Hepatology, 2017, 65(5): 1683-1692. DOI: 10.1002/hep.28990.
    [11] RODRÍGUEZ-VILARRUPLA A, FERNÍNDEZ M, BOSCH J, et al. Current concepts on the pathophysiology of portal hypertension[J]. Ann Hepatol, 2007, 6(1): 28-36. http://www.annalsofhepatology.com/PDF/vol6n1/Hp071-05.pdf
    [12] SHENODA B, BOSELLI J. Vascular syndromes in liver cirrhosis[J]. Clin J Gastroenterol, 2019, 12(5): 387-397. DOI: 10.1007/s12328-019-00956-0.
    [13] RAEVENS S, GEERTS A, van STEENKISTE C, et al. Hepatopulmonary syndrome and portopulmonary hypertension: Recent knowledge in pathogenesis and overview of clinical assessment[J]. Liver Int, 2015, 35(6): 1646-1660. DOI: 10.1111/liv.12791.
    [14] TERAO M, TAKAKI A, MARUYAMA T, et al. Serum oxidative/anti-oxidative stress balance is dysregulated in potentially pulmonary hypertensive patients with liver cirrhosis: A case control study[J]. Intern Med, 2015, 54(22): 2815-2826. DOI: 10.2169/internalmedicine.54.4889.
    [15] MAIR KM, JOHANSEN AK, WRIGHT AF, et al. Pulmonary arterial hypertension: Basis of sex differences in incidence and treatment response[J]. Br J Pharmacol, 2014, 171(3): 567-579. DOI: 10.1111/bph.12281.
    [16] SEHGAL PB, YANG YM, MILLER EJ. Hypothesis: Neuroendocrine mechanisms (hypothalamus-growth hormone-STAT5 axis) contribute to sex bias in pulmonary hypertension[J]. Mol Med, 2015, 21(1): 688-701. DOI: 10.2119/molmed.2015.00122.
    [17] AL-NAAMANI N, KROWKA MJ, FORDE KA, et al. Estrogen signaling and portopulmonary hypertension: The pulmonary vascular complications of liver disease study (PVCLD2)[J]. Hepatology, 2021, 73(2): 726-737. DOI: 10.1002/hep.31314.
    [18] KAWUT SM, KROWKA MJ, TROTTER JF, et al. Clinical risk factors for portopulmonary hypertension[J]. Hepatology, 2008, 48(1): 196-203. DOI: 10.1002/hep.22275.
    [19] AUSTIN ED, LOYD JE. The genetics of pulmonary arterial hypertension[J]. Circ Res, 2014, 115(1): 189-202. DOI: 10.1161/CIRCRESAHA.115.303404.
    [20] International PPH Consortium, LANE KB, MACHADO RD, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension[J]. Nat Genet, 2000, 26(1): 81-84. DOI: 10.1038/79226.
    [21] DENG Z, MORSE JH, SLAGER SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-Ⅱ gene[J]. Am J Hum Genet, 2000, 67(3): 737-744. DOI: 10.1086/303059.
    [22] NIKOLIC I, YUNG LM, YANG P, et al. Bone morphogenetic protein 9 is a mechanistic biomarker of portopulmonary hypertension[J]. Am J Respir Crit Care Med, 2019, 199(7): 891-902. DOI: 10.1164/rccm.201807-1236OC.
    [23] WANG RN, GREEN J, WANG Z, et al. Bone morphogenetic protein (BMP) signaling in development and human diseases[J]. Genes Dis, 2014, 1(1): 87-105. DOI: 10.1016/j.gendis.2014.07.005.
    [24] MILLER AF, HARVEY SA, THIES RS, et al. Bone morphogenetic protein-9. An autocrine/paracrine cytokine in the liver[J]. J Biol Chem, 2000, 275(24): 17937-17945. DOI: 10.1074/jbc.275.24.17937.
    [25] SCHARPFENECKER M, van DINTHER M, LIU Z, et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis[J]. J Cell Sci, 2007, 120(Pt 6): 964-972. DOI: 10.1242/jcs.002949.
    [26] DAVID L, MALLET C, MAZERBOURG S, et al. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1(ALK1) in endothelial cells[J]. Blood, 2007, 109(5): 1953-1961. DOI: 10.1182/blood-2006-07-034124.
    [27] CONSTAM DB, ROBERTSON EJ. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases[J]. J Cell Biol, 1999, 144(1): 139-149. DOI: 10.1083/jcb.144.1.139.
    [28] BROWN MA, ZHAO Q, BAKER KA, et al. Crystal structure of BMP-9 and functional interactions with pro-region and receptors[J]. J Biol Chem, 2005, 280(26): 25111-25118. DOI: 10.1074/jbc.M503328200.
    [29] CHEN C, GRZEGORZEWSKI KJ, BARASH S, et al. An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis[J]. Nat Biotechnol, 2003, 21(3): 294-301. DOI: 10.1038/nbt795.
    [30] CHEN H, BRADY RIDGWAY J, SAI T, et al. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development[J]. Proc Natl Acad Sci U S A, 2013, 110(29): 11887-11892. DOI: 10.1073/pnas.1306074110.
    [31] LÓPEZ-COVIELLA I, BERSE B, KRAUSS R, et al. Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9[J]. Science, 2000, 289(5477): 313-316. DOI: 10.1126/science.289.5477.313.
    [32] PARK JE, SHAO D, UPTON PD, et al. BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production[J]. PLoS One, 2012, 7(1): e30075. DOI: 10.1371/journal.pone.0030075.
    [33] SHAO D, PARK JE, WORT SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension[J]. Pharmacol Res, 2011, 63(6): 504-511. DOI: 10.1016/j.phrs.2011.03.003.
    [34] UPTON PD, PARK J, de SOUZA PM, et al. Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells[J]. J Cell Sci, 2020, 133(14): jcs239715. DOI: 10.1242/jcs.239715.
    [35] CHEN X, ORRIOLS M, WALTHER FJ, et al. Bone morphogenetic protein 9 protects against neonatal hyperoxia-induced impairment of alveolarization and pulmonary inflammation[J]. Front Physiol, 2017, 8: 486. DOI: 10.3389/fphys.2017.00486.
    [36] HERRERA B, DOOLEY S, BREITKOPF-HEINLEIN K. Potential roles of bone morphogenetic protein (BMP)-9 in human liver diseases[J]. Int J Mol Sci, 2014, 15(4): 5199-5220. DOI: 10.3390/ijms15045199.
    [37] WIERCINSKA E, WICKERT L, DENECKE B, et al. Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells[J]. Hepatology, 2006, 43(5): 1032-1041. DOI: 10.1002/hep.21135.
    [38] LONG L, ORMISTON ML, YANG X, et al. Selective enhancement of endothelial BMPR-Ⅱ with BMP9 reverses pulmonary arterial hypertension[J]. Nat Med, 2015, 21(7): 777-785. DOI: 10.1038/nm.3877.
    [39] ORMISTON ML, UPTON PD, LI W, et al. The promise of recombinant BMP ligands and other approaches targeting BMPR-Ⅱ in the treatment of pulmonary arterial hypertension[J]. Glob Cardiol Sci Pract, 2015, 2015(4): 47. DOI: 10.5339/gcsp.2015.47.
    [40] ATKINSON C, STEWART S, UPTON PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type Ⅱ bone morphogenetic protein receptor[J]. Circulation, 2002, 105(14): 1672-1678. DOI: 10.1161/01.cir.0000012754.72951.3d.
    [41] DAVID L, MALLET C, KERAMIDAS M, et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor[J]. Circ Res, 2008, 102(8): 914-922. DOI: 10.1161/CIRCRESAHA.107.165530.
    [42] MORRELL NW, BLOCH DB, TEN DIJKE P, et al. Targeting BMP signalling in cardiovascular disease and anaemia[J]. Nat Rev Cardiol, 2016, 13(2): 106-120. DOI: 10.1038/nrcardio.2015.156.
    [43] MA C, WANG H. Research progress of BMP9 and liver diseases[J]. Chin Pharmacol Bull, 2020, 36(8): 1045-1048. DOI: 10.3969/j.issn.1001-1978.2020.08.003.

    马翠, 王华. BMP9与肝脏疾病的研究进展[J]. 中国药理学通报, 2020, 36(8): 1045-1048. DOI: 10.3969/j.issn.1001-1978.2020.08.003.
    [44] WANG G, FAN R, JI R, et al. Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: A case report[J]. BMC Pulm Med, 2016, 16: 17. DOI: 10.1186/s12890-016-0183-7.
    [45] HODGSON J, SWIETLIK EM, SALMON RM, et al. Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2020, 201(5): 575-585. DOI: 10.1164/rccm.201906-1141OC.
    [46] STAR GP, GIOVINAZZO M, LANGLEBEN D. Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells: A potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension[J]. Microvasc Res, 2010, 80(3): 349-354. DOI: 10.1016/j.mvr.2010.05.010.
    [47] CACOUB P, DORENT R, NATAF P, et al. Endothelin-1 in the lungs of patients with pulmonary hypertension[J]. Cardiovasc Res, 1997, 33(1): 196-200. DOI: 10.1016/s0008-6363(96)00189-7.
    [48] YOSHIBAYASHI M, NISHIOKA K, NAKAO K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation[J]. Circulation, 1991, 84(6): 2280-2285. DOI: 10.1161/01.cir.84.6.2280.
    [49] HONG C, CHEN HM, QI XL. Diagnosis and treatment strategies of portopulmonary hypertension[J]. Chin J Dig Surg, 2021, 20(10): 1042-1046. DOI: 10.3760/cma.j.cn115610-20210722-00359.

    洪城, 陈海明, 祁小龙. 门静脉高压相关性肺动脉高压的诊断与治疗策略[J]. 中华消化外科杂志, 2021, 20(10): 1042-1046. DOI: 10.3760/cma.j.cn115610-20210722-00359.
    [50] DUNMORE BJ, DRAKE KM, UPTON PD, et al. The lysosomal inhibitor, chloroquine, increases cell surface BMPR-Ⅱ levels and restores BMP9 signalling in endothelial cells harbouring BMPR-Ⅱ mutations[J]. Hum Mol Genet, 2013, 22(18): 3667-3679. DOI: 10.1093/hmg/ddt216.
    [51] TU L, DESROCHES-CASTAN A, MALLET C, et al. Selective BMP-9 inhibition partially protects against experimental pulmonary hypertension[J]. Circ Res, 2019, 124(6): 846-855. DOI: 10.1161/CIRCRESAHA.118.313356.
    [52] BOUVARD C, TU L, ROSSI M, et al. Different cardiovascular and pulmonary phenotypes for single-and double-knock-out mice deficient in BMP9 and BMP10[J]. Cardiovasc Res, 2021. DOI:10.1093/cvr/cvab187.[Online ahead of print]
  • 加载中
图(3)
计量
  • 文章访问数:  383
  • HTML全文浏览量:  157
  • PDF下载量:  34
  • 被引次数: 0
出版历程
  • 收稿日期:  2021-07-24
  • 录用日期:  2021-09-08
  • 出版日期:  2022-03-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回